Shp2, encoded by the PTPN11 gene, is a non-receptor PTP with two Src homology-2 (SH2) domains (N-SH2, C-SH2) (Alonso et al., 2004; Neel et al., 2003). Molecular biology and genetic studies has shown that Shp2 mediates cell signaling by growth factors and cytokines, such as epidermal growth factor (EGF), hepatocyte growth factor, and interleukin-6. In particular, Shp2 is involved in activation of Erk1/2 MAP kinase by EGF (Deb et al., 1998).
Shp2 is basally inactive due to auto-inhibition by its N-SH2 domain (Hof et al., 1998). In growth factor- and cytokine-stimulated cells, Shp2 binds to tyrosine-phosphorylated docking proteins through its SH2 domains, resulting in its activation (Cunnick et al., 2001). It has been shown that Shp2 binds to Gab1 (or Gab2) in cells stimulated with EGF, HGF, or interleukin-6 (Cunnick et al., 2001; Gu and Neel, 2003; Maroun et al., 2000; Nishida and Hirano, 2003). Gab1-Shp2 interaction as well as Shp2 PTP activity are necessary for Erk1/2 activation by these growth factors (Cunnick et al., 2002; Neel et al., 2003). While the mechanism by which growth factors activate Shp2 has been elucidated, those by which Shp2 produces downstream signals to activate Ras-Erk1/2 MAP kinase pathway and possibly other pathways are less clear and may be growth factor- and cell context-dependent (Mohi et al., 2005).
Besides its role in growth factor and cytokine signaling, Shp2 has been implicated in pathogenicity of H. pylori. Cytotoxin-associated antigen A (CagA)-positive strains of H. pylori are strongly associated with gastritis and gastric cancer. After injected into host cells, CagA is retained on the plasma membrane and recruits Shp2 to induce transformation of gastric epithelial cells (Hatakeyama, 2004).
Remarkably, PTPN11 mutations have been found in Noonan syndrome, juvenile myelomonocytic leukemia (JMML), and several types of human malignancies (Bentires-Alj et al., 2004; Tartaglia and Gelb, 2005). Noonan syndrome is a developmental disorder characterized by facial anomalies, short stature, heart disease, skeletal defects, and hematological disorders (Tartaglia and Gelb, 2005). Germline PTPN11 mutations are responsible for causing 50% of cases of Noonan syndrome. Some children with Noonan syndrome also develop JMML (Tartaglia et al., 2003). JMML is a progressive myelodysplastic/myeloproliferative disorder characterized by overproduction of tissue-infiltrating myeloid cells. Approximately 50% of cases of JMML have activating Ras mutations or homozygotic inactivation of the NF1 gene that encodes a Ras-GTPase activating protein, neurofibromin. Somatic mutations in PTPN11 account for about 35% of JMML patients who do not have Ras or neurofibromin mutations (Kratz et al., 2005). It was reported recently that JMML-associated Shp2 mutants could transform murine bone marrow and fetal liver cells (Chan et al., 2005; Mohi et al., 2005; Schubbert et al., 2005) and caused fatal JMML-like disorder in Balb/c mice (Mohi et al., 2005). While molecular etiologies of Noonan syndrome and JMML are becoming clear, several mechanistic issues regarding how Shp2 mutants cause Noonan syndrome and JMML remain unanswered. Importantly, all Shp2 mutants found in Noonan syndrome and JMML are gain-of-function mutations, mostly resulting from weaker autoinhibition of the N-SH2 domain (Fragale et al., 2004; Keilhack et al., 2005).
In short, accumulated molecular biology and genetic evidence has suggested that Shp2 is an important signaling component of growth factors, cytokines, and oncogenic bacteria. Gain-of-function Shp2 mutations are linked to childhood developmental disorder and juvenile leukemias. Therefore, Shp2 PTP is an important target for controlling growth factor receptor signaling and a potential target for development of novel therapies for Noonan syndrome, JMML, and possibly other Shp2-associated cancers.
PTP inhibitor development is an emerging area in the field of drug development (Bialy and Waldmann, 2005). Most efforts of PTP inhibitor discovery and design have so far been focused on PTP1B and Cdc25 inhibitors (Lazo et al., 2002; Zhang, 2002). No systematic effort to identify Shp2-selective PTP inhibitors has been reported. While PTP1B inhibitors that cross-inhibit Shp2 have been found (Huang et al., 2003; Shen et al., 2001), none of them has demonstrated in vivo activity in cell cultures.